The proposed research has three broad aims: first, it will continue to characterize parameters of tolerance to the stimulus effects of cocaine, including determination of whether tolerance occurs to the reinforcing effects of cocaine in rats working under a progressive-ratio (PR) schedule; second, patterns of tolerance and cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine will be determined following high-dose treatment with other drugs of abuse; and third, selective dopaminergic agonists and antagonists will be used to investigate the role of dopaminergic receptor subtypes in the development of tolerance and sensitization to the discriminative and reinforcing stimulus effects of cocaine. The proposed experiments use rats as subjects; they will be used in drug discrimination and drug self- administration studies, with the latter studies using both low-value fixed-ratio (FR) as well as PR schedules. In discrimination experiments, rats are trained to discriminate cocaine from saline using a two-lever choice procedure. In self-administration experiments, rats are implanted with i.v. catheters and trained to press a lever with an injection of cocaine serving as the reinforcer. Initially, the time course for the development of tolerance to the reinforcing effects of cocaine will be determined. Rats trained under the FR procedure will be made tolerant by permitting free access to cocaine, 0.25 mg/injection for periods up to 12 hr per day. In subsequent experiments, patterns of cross-tolerance will be tested by determining the extent to which high-dose administration of various drugs of abuse leads to tolerance to the effects of cocaine (measured in the discrimination and self- administration paradigms, both FR and PR). In addition, other subjects will be trained to self-administer heroin, and they will be used to test the hypothesis that tolerance to the reinforcing effects of cocaine (produced by administering cocaine, 20 mg/kg/8-hr for a minimum of 4 days) confers cross-tolerance to the reinforcing effects of heroin. Sensitivity to the discriminative stimulus effects of cocaine is known to show either tolerance or sensitization following chronic treatment with dopaminergic agonists or antagonists, respectively. The final portion of these experiments will determine whether this same pattern of results is seen in animals self-administering cocaine when they are exposed to these dopaminergic agents. The proposed experiments are important because tolerance to the reinforcing effects of drugs has only recently been demonstrated: the extent to which tolerance occurs, the pattern of drugs that share cross-tolerance, and the neurochemical mechanisms mediating this effect may all be important information for understanding the determinants of chronic, high-dose drug use.
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